Macrophages include a heterogeneous population of cells found in most tissues of the body. These cells are capable of performing a broad spectrum of functions. Macrophage phenotypes are classified along a continuum between the extremes of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages.
Macrophages are induced to a pro-inflammatory M1 state by Th1 cytokines (such as IFNγ and TNFα) and bacterial products (such as LPS). M1 macrophages play major roles in host defense against bacteria and tissue remodeling post-injury through production of pro-inflammatory cytokines (such as IL12, TNFα, and IL1), reactive oxygen species (ROS) and nitric oxide (NO), and proteases (such as MMP 2 and 9). A combination of stimuli including Th2 cytokines (such as IL4, IL10 and IL13), growth factors (such as TGFβ and CSF1), glucocorticoids, and immune complexes, can polarize macrophages toward an anti-inflammatory M2 phenotype. M2 macrophages play major roles in tissue homeostasis and repair, inflammation resolution, and immune regulation.
The seemingly opposing functions of M1 and M2 macrophages must be tightly regulated for an effective and proper response to foreign molecules or damaged tissue. Excessive activation of either M1 or M2 macrophages contributes to the pathology of many diseases. For instance, chronic M1 macrophage activation promotes tissue damage in neurodegenerative disorders, arthritis, and autoimmune diseases. While necessary for the initial stages of tissue repair, an excessive M1 activation inhibits the healing of damaged tissue through excessive matrix degradation and inhibition of tissue regeneration. Chronic M1 activation has also been shown to promote the development of cancer. Increased inflammatory monocyte/macrophage infiltration has been shown to correlate with disease severity for patients with myocardial infarction, atherosclerosis, and metabolic disorders.
Prolonged or excessive M2 macrophage activation has also been shown to be detrimental. M2 macrophages contribute to lung inflammation and damage in allergy and asthma. They have also been shown to impair tissue functions through promoting fibrosis. M2 macrophage infiltration correlates with increased cancer growth and metastasis in multiple types of cancer. They are shown to promote cancer growth and metastasis by supporting ECM remodeling, angiogenesis, and immune suppression.
Macrophage infiltration has been correlated with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing anti-tumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. For instance, breast cancer tumor growth and metastasis depend on the support from stromal cells, including macrophages, fibroblasts, and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) which promote angiogenesis, matrix remodeling, and immunosuppression.
Macrophages are also able to retain a memory for the signals that they have been exposed to through epigenetic modification, which results in increased transcription (priming) or repressed transcription (tolerance) upon future exposure. Cytokines cause the epigenetic modification through addition of positive histone modifications H3K4m3 or H3K27ac to gene promoters, which lead to increased expression. The mechanisms of tolerance are incompletely understood but are believed to involve the loss of positive histone modifications and/or an increase in negative histone modifications (such as H3K27m3).
There has been growing interest in immunotherapies for the treatment of cancers including breast cancer because of their low toxicity and extended duration of action. Unfortunately, the immunosuppressive microenvironment of tumors greatly diminishes the effectiveness of these therapies. MDSCs, M2-like tumor-associated macrophages (TAMs), and regulatory T cells have all been shown to repress an effective anti-tumor immune response through the production of anti-inflammatory cytokines and growth factors such as IL10 and TGFβ. Therapies targeting the immunosuppressive microenvironment have shown great potential on their own or in combination with other therapies in experimental models.
There has also been growing interest in herb derived compounds as they can modulate multiple inflammatory pathways, are inexpensive, and have low toxicity for chronic treatment. Emodin is a trihydroxy-anthraquinone which is found in several Chinese herbs including rhubarb (Rheum palmatum) and tuber fleece flower (Polygonam multiflorum, also commonly known as Chinese knotweed or he shou wu). Emodin has shown potential to inhibit inflammation in various settings. For instance, emodin has been shown to attenuate the severity of experimental disease models including arthritis, liver damage, atherosclerosis, myocardial ischemia, and cancer.
What are needed in the art are methods and materials that can inhibit a broad range of macrophage phenotypes through regulation of multiple signaling pathways. Such a compound would have great clinical potential.